Loss of Ptf1a Leads to a Widespread Cell-Fate Misspecification in the Brainstem, Affecting the Development of Somatosensory and Viscerosensory Nuclei
Loss of Ptf1a Leads to a Widespread Cell-Fate Misspecification in the Brainstem, Affecting the Development of Somatosensory and Viscerosensory Nuclei
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DOI：
10.1523/jneurosci.2526-15.2016
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发表时间：
2016-03-02
影响因子：
5.3
通讯作者：
Chizhikov, Victor V.
中科院分区：
文献类型：
--
作者：
Iskusnykh, Igor Y.;Steshina, Ekaterina Y.;Chizhikov, Victor V.
脑干包含不同的神经元群体，调节对生物体至关重要的广泛过程。正确的细胞命运规范的决定是至关重要的，以实现中枢神经系统的神经元多样性，但在发育中的脑干调控细胞命运规范的机制知之甚少。以前，它已被证明，碱性螺旋-环-螺旋转录因子Ptf 1a是所需的下橄榄和耳蜗脑干核，这有助于运动协调和声音处理，分别神经元的分化和生存。在这项研究中，我们表明，Ptf 1a的损失损害孤束核，其中处理内脏感觉信息，和脊髓和三叉神经主核，其中集成的躯体感觉信息的脸的发展。结合遗传命运图谱、出生日期和基因表达研究，我们发现Ptf 1a（-/-）小鼠中至少有一部分脑干异常是由菱体2-7中显著的细胞命运错误指定介导的，这导致Lmx 1b谱系的多余内脏感觉和躯体感觉神经元的产生，而Pax 2（+）GABA能内脏感觉和躯体感觉神经元的产生是以Pax 2（+）GABA能内脏感觉和躯体感觉神经元为代价的，和下橄榄核神经元。我们的数据确定Ptf 1a作为一个主要的调节器的细胞命运规范的决定，在发展中的脑干，作为一个以前未被认识到的发展调节器的内脏感觉和体感脑干核。
The brainstem contains diverse neuronal populations that regulate a wide range of processes vital to the organism. Proper cell-fate specification decisions are critical to achieve neuronal diversity in the CNS, but the mechanisms regulating cell-fate specification in the developing brainstem are poorly understood. Previously, it has been shown that basic helix-loop-helix transcription factor Ptf1a is required for the differentiation and survival of neurons of the inferior olivary and cochlear brainstem nuclei, which contribute to motor coordination and sound processing, respectively. In this study, we show that the loss of Ptf1a compromises the development of the nucleus of the solitary tract, which processes viscerosensory information, and the spinal and principal trigeminal nuclei, which integrate somatosensory information of the face. Combining genetic fate-mapping, birth-dating, and gene expression studies, we found that at least a subset of brainstem abnormalities in Ptf1a(-/-) mice are mediated by a dramatic cell-fate misspecification in rhombomeres 2-7, which results in the production of supernumerary viscerosensory and somatosensory neurons of the Lmx1b lineage at the expense of Pax2(+) GABAergic viscerosensory and somatosensory neurons, and inferior olivary neurons. Our data identify Ptf1a as a major regulator of cell-fate specification decisions in the developing brainstem, and as a previously unrecognized developmental regulator of both viscerosensory and somatosensory brainstem nuclei.